title: Plasminogen activator inhibitor-1 antagonist TM5441 attenuates Nω-nitro-L-arginine methyl ester-induced hypertension and vascular senescence.
abstract: BACKGROUND
  Long-term inhibition of nitric oxide synthase by L-arginine analogues such as N(ω)-nitro-l-arginine methyl ester (L-NAME) has been shown to induce senescence in vitro and systemic hypertension and arteriosclerosis in vivo. We previously reported that plasminogen activator inhibitor-1 (PAI-1)-deficient mice (PAI-1(-/-)) are protected against L-NAME-induced pathologies. In this study, we investigated whether a novel, orally active PAI-1 antagonist (TM5441) has a similar protective effect against L-NAME treatment. Additionally, we studied whether L-NAME can induce vascular senescence in vivo and investigated the role of PAI-1 in this process.
  
  
  RESULTS
  Wild-type mice received either L-NAME or L-NAME and TM5441 for 8 weeks. Systolic blood pressure was measured every 2 weeks. We found that TM5441 attenuated the development of hypertension and cardiac hypertrophy compared with animals that had received L-NAME alone. Additionally, TM5441-treated mice had a 34% reduction in periaortic fibrosis relative to animals on L-NAME alone. Finally, we investigated the development of vascular senescence by measuring p16(Ink4a) expression and telomere length in aortic tissue. We found that L-NAME increased p16(Ink4a) expression levels and decreased telomere length, both of which were prevented with TM5441 cotreatment.
  
  
  CONCLUSIONS
  Pharmacological inhibition of PAI-1 is protective against the development of hypertension, cardiac hypertrophy, and periaortic fibrosis in mice treated with L-NAME. Furthermore, PAI-1 inhibition attenuates the arterial expression of p16(Ink4a) and maintains telomere length. PAI-1 appears to play a pivotal role in vascular senescence, and these findings suggest that PAI-1 antagonists may provide a novel approach in preventing vascular aging and hypertension.
authors.affiliation: Department of Medicine (A.E.B., M.E., S.B.M., C.E.K., D.E.V.) and Feinberg Cardiovascular Research Institute (A.E.B., S.B.M., C.E.K., D.E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL; United Centers for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine, Miyagi, Japan (A.I., T.M.); and Conrad Prebys Center for Chemical Genomics (D.T., D.M., L.H.S.) and Cardiopathobiology Program, Diabetes and Obesity Research Center (D.M., L.H.S.), Sanford Burnham Medical Research Institute at Lake Nona, Orlando FL.
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Boe
authors.forename: Mesut
authors.initials: M
authors.lastname: Eren
authors.forename: Sheila B
authors.initials: SB
authors.lastname: Murphy
authors.forename: Christine E
authors.initials: CE
authors.lastname: Kamide
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Ichimura
authors.forename: David
authors.initials: D
authors.lastname: Terry
authors.forename: Danielle
authors.initials: D
authors.lastname: McAnally
authors.forename: Layton H
authors.initials: LH
authors.lastname: Smith
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000188:drug therapy; D016922:Cellular Senescence / Q000187:drug effects*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D010879:Piperazines / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D058258:Serpin E2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D016615:Telomere / Q000187:drug effects; D062366:para-Aminobenzoates / Q000737:chemistry
chemical_list: C549556:5-chloro-2-(((2-(4-(diphenylmethyl)piperazin-1-yl)-2-oxoethoxy)acetyl)amino)benzoate; D004791:Enzyme Inhibitors; D010879:Piperazines; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D062366:para-Aminobenzoates; D019331:NG-Nitroarginine Methyl Ester
keywords: aging; hypertension; nitric oxide synthase